Cancer combat is a great challenge for human beings, and to this end, chemotherapeutic drugs are still vigorously developed. However, the reality is that pharmaceuticals which have cancer cell-specific effects have not been created yet. Recently, it is known that the inside of tumors is partially hypoxic because neovascular network in tumors is disorderly formed from structurally fragile blood vessels. Since hypoxic cancer cells adapt to hypoxic conditions by metabolism alteration and actively produce proangiogenic factors and cancer metastasis-related factors, hypoxia is considered to greatly contribute to cancer aggravation.
HIF-1 (Hypoxia Inducible Factor-1) is known as a transcription factor which plays a crucial role in the hypoxic adaptation of cancer cells. HIF-1 functions as a heterodimer of an alpha subunit and a beta subunit, but under normal conditions, the alpha subunit is deficient because oxidative degradation of the alpha subunit is enhanced. Meanwhile, under hypoxia, the oxidative degradation is reduced and the two subunits form a heterodimer, which is an active-form HIF-1. The active-form HIF-1 increases the expressions of factors required for hypoxic adaptation and of angiogenesis- or metastasis-promoting factors by binding to HRE (hypoxia response element) in the respective promoter regions (see Non Patent Literature 1). Based on these findings as well as the facts that hypoxia is an environment specific to tumors and hardly exists under physiological conditions, many exploratory studies on compounds targeting HIF-1 or its related molecules have been carried out (see Non Patent Literature 2 and 3). However, since the whole mechanism for hypoxic adaptation of cancer cells has not been clarified, drug development based on other targets than HIF-1 or its related molecules has hardly been conducted. Moreover, no single pharmaceutical that inhibits HIF-1 or its related molecules has been marketed yet. As understood from the above, it is a crucial issue to create novel pharmaceuticals which are different in chemical structure and action mechanism from existing compounds.
Under such circumstances, the present inventors found that human prostate cancer DU-145 cells cultured under hypoxic conditions of the oxygen level of 1% can adapt to hypoxia via increased expression of HIF-1 alpha, and based on the use of these cells, constructed an assay system to screen for compounds which selectively inhibit cell growth under hypoxic conditions. By using the assay system, the present inventors screened various natural substance libraries, and as a result, found that the extract from a marine sponge inhabiting Indonesia has such an inhibitory activity. The present inventors fractionated and purified the extract using the activity test results as an indicator, and identified a substance having selective inhibitory activity on hypoxic cell growth, as furospinosulin-1, a furanosesterterpene represented by the following formula (see Non Patent Literature 4).

The present inventors found that furospinosulin-1 not only inhibits in vitro cancer cell growth in a hypoxia-selective manner, but also significantly reduces in vivo tumor weight in mice subcutaneously inoculated with mouse sarcoma S180 cells as compared with the control. In addition, the present inventors revealed that the mechanism of these actions is based on the inhibition of hypoxia-inducible expression of insulin-like growth factor 2 (IGF-2), not on the inhibition of HIF-1 or its related molecules (see Non Patent Literature 4).
However, furospinosulin-1 at 1000 μM shows equal growth inhibitory activity against normoxic cells and hypoxic cells. Therefore, desired are novel compounds with higher safety, i.e., compounds which maintain hypoxic selectivity even in a high concentration.